The aggressive cancer cell phenotype is the result of a variety of genetic and epigenetic alterations leading to deregulation of intracellular signaling pathways (Ponder, Nature 411:336 (2001)). Cancer cells typically fail to execute an apoptotic program, and lack of appropriate apoptosis due to defects in the normal apoptosis machinery is considered a hallmark of cancer (Lowe et al., Carcinogenesis 21:485 (2000)). The inability of cancer cells to execute an apoptotic program due to defects in the normal apoptotic machinery often is associated with an increase in resistance to chemotherapy, radiation, or immunotherapy-induced apoptosis. Primary or acquired resistance of human cancer of different origins to current treatment protocols due to apoptosis defects is a major problem in current cancer therapy (Lowe et al., Carcinogenesis 21:485 (2000); Nicholson, Nature 407:810 (2000)). Accordingly, current and future efforts directed to designing and developing new molecular target-specific anticancer therapies to improve survival and quality of life of cancer patients must include strategies that specifically target cancer cell resistance to apoptosis.
The p53 tumor suppressor plays a central role in controlling cell cycle progression, senescence, and apoptosis (Vogelstein et al., Nature 408:307 (2000); Goberdhan, Cancer Cell 7:505 (2005)). MDM2 and p53 are part of an auto-regulatory feed-back loop (Wu et al., Genes Dev. 7:1126 (1993)). MDM2 is transcriptionally activated by p53 and MDM2, in turn, inhibits p53 activity by at least three mechanisms (Wu et al., Genes Dev. 7:1126 (1993)). First, MDM2 protein directly binds to the p53 transactivation domain, and thereby inhibits p53-mediated transactivation. Second, MDM2 protein contains a nuclear export signal sequence, and upon binding to p53, induces the nuclear export of p53, preventing p53 from binding to the targeted DNAs. Third, MDM2 protein is an E3 ubiquitin ligase and upon binding to p53 is able to promote p53 degradation.
Although high-affinity peptide-based inhibitors of MDM2 have been successfully designed in the past (Garcia-Echeverria et al., Med. Chem. 43:3205 (2000)), these inhibitors are not suitable therapeutic molecules because of their poor cell permeability and in vivo bioavailability. In the last few years, there have been reports of discoveries of potent, non-peptide, small-molecule MDM2 inhibitors. See e.g., U.S. Pat. Nos. 7,851,626; 8,088,815; 7,759,383; 7,737,174; and 8,629,141; U.S. Pat. Appl. Publ. Nos. 2012/0046306; 2010/0152190; 2011/0112052; 2012/0122947; Int. Pat. Appl. Publ. WO 2011/153509; WO 2013/049250; literature, Vassilev et al. Science 2004, 303, 844-48; Vu, et al. ACS Med. Chem. Lett., 2013, 4 (5), 466-69; Zhang, et al. ACS Med. Chem. Lett., 2014, 5 (2), 124-27; Ding et. al., J. Med. Chem., 2013, 56 (14), 5979-83; Shu, et al. Org. Process Res. Dev., 2013, 17 (2), 247-56; Zhao, et al. J. Med. Chem., 2013, 56 (13), 5553-61; Zhao, et al. J. Am. Chem. Soc., 2013, 135 (19), 7223-34; Sun et al. J. Med. Chem., 2014, 57 (4), 1454-72; Turiso et al., J. Med. Chem., 2013, 56 (10), 4053-70; and Rew et al. J. Med. Chem., 2012, 55 (11), 4936-54). Despite these major advances, there is still a need to identify potent, non-peptide MDM2 inhibitors having suitable physiochemical and pharmacological properties that permit use of the inhibitors in therapeutic applications.
The present invention provides compounds designed to inhibit MDM2-p53 interactions, and therefore activate the function of p53 and p53-related proteins for therapeutic applications.